This proposal seeks funding to continue the observational follow-up of the 81,501 middle-aged and older Chinese men and women participants of the Shanghai and Singapore cohort studies for another 5 five years, to accrue and validate a substantially increased number of cancer endpoints in order to evaluate important questions related to lifestyle, biochemical markers, genetic markers, and gene-environment interactions on cancer risk. The Shanghai cohort was assembled in 1986-1989 and the Singapore cohort in 1993-1998. In addition to data collected at baseline and follow-up interviews, blood and urine samples were collected from more than 50,000 subjects at baseline and stored in ultra-low temperature condition since their collection. The vigorous and effective follow-up procedures kept the loss of follow-up to be minimal; to date, only approximately 880 (1%) original cohort participants have been lost to follow-up over the past 20 years. These databases have been serving unique resources for a large number of projects for research on cancer etiology and prevention. In the next 5 five years, we also propose to conduct a series of nested case-control studies within the two cohorts to elucidate the role of environmental exposure, genetic variants and DNA methylation in the development of lung or liver cancer. The primary scientific aims are: (1) to assess the independent role of polycyclic aromatic hydrocarbons (PAH), 1,3-butadiene, acrolein, benzene, and ethylene oxide in the development of lung cancer among smokers; (2) to assess independent role of PAH, 1,3-butadiene, acrolein, benzene, and ethylene oxide in the development of lung cancer among lifelong nonsmokers; (3) to assess the role of methyl groups - S-adenosylmethionine, S-adenosylhomocysteine, methionine, choline, homocysteine, folate, vitamins B6 and B12 in the development of liver cancer; (4) to assess the role of genetic polymorphisms influencing methyl group metabolism in the development of liver cancer, and their modifying effect on the associations between methyl groups and liver cancer risk; and (5) to assess the role of global DNA hypomethylation in the development of liver cancer. The proposed studies with prospective study design, available pre-diagnostic blood and urine samples, and large sample sizes will provide novel and definitive data to accomplish these scientific aims. Furthermore, findings of the proposed studies will provide insights for the understanding of the role of methyl groups, the donor of DNA methylation, in human hepatocarcinogenesis. The ultimate goal of the proposed research is the development of an effective set of non-invasive, predictive markers that allow for the identification of the relatively small fraction of individuals who are at very high risk for lung or liver cancer. People with high risk could take primary preventive measures to reduce their risk, or undergo regular screening for early detection of the malignancies when clinical treatment is more effective. PUBLIC HEALTH RELEVANCE: The Shanghai and Singapore cohort studies are ongoing observational follow-up investigation of environmental and genetic factors on human cancers in 81,501 middle-aged and older Chinese men and women beginning in 1986 and 1993, respectively. The proposed studies within these two cohorts will identify a set of non-invasive, predictive markers of lung and liver cancer development. People with high risk could take primary preventive measures to reduce their risk, or undergo regular screening for early detection of the malignancies when clinical treatment is more effective. The findings of the proposed study will have great impact on reducing incidence and mortality of lung and liver cancers in humans.